Human tumor necrosis factor-α (hereinafter referred to as “hTNFα”) is a homotrimer consisting of three 17 kDa protein subunits (Eck M J et al., JBC 267: 2119–2122, 1992; Smith R A et al., JBC 262: 6951–6954, 1987). hTNFα is an inflammatory cytokine secreted from monocytes and macrophages and functions as a signal transmitter in several cellular reactions such as necrosis and apoptosis (Beyaert R et al., FEBS Lett. 340: 9–16, 1994).
hTNFα causes a pro-inflammatory action leading to tissue destruction, such as breakdown of the cartilage and bone (Saklatvala, Nature 322: 547–549, 1986) and increasing the adherence of neutrophils and lymphocytes (Pober et al., K. Immunol. 138: 3319, 1987). In addition, it has been known that hTNFα plays an important role in a defense mechanism against infectious disease and tumor (Fiers W, FEBS Lett. 285: 199–212, 1991).
hTNFα is involved in inflammatory diseases, autoimmune diseases, bacterial infections, cancers and degenerative diseases. Among these diseases, hTNFα has been regarded as a useful target protein for a specific physiological treatment of rheumatoid arthritis and Crohn's disease.
Meanwhile, it has been also suggested to use a hTNFα inhibitor for the purpose of treating rheumatoid arthritis. It has been reported that hTNFα is overexpressed in the synovial cells isolated from the early-stage rheumatoid joint (Buchan G et al., Clin. Exp. Immunol. 73: 449–455, 1988), and cytokines relating to rheumatoid arthritis lesions are decreased when the above synovial cells are treated with an anti-hTNFα monoclonal antibody (Butler D M et al., Eur. Cytokine Netw. 6: 225–230, 1995).
Further, it has been found that an anti-hTNFα antibody or a recombinant soluble hTNFα receptor suppresses inflammation and destruction of a joint in a collagen induced mouse arthritis model (Wpiquet P F et al., Immunology 77: 510–514, 1992; Wooley P H et al., J. Immunol. 151: 6602–6607, 1993; Williams R O et al., Immunology 84: 433–439, 1995). Moreover, it has been observed that inflammatory arthritis is induced in a transgenic mouse overexpressing hTNFα (Keffer J et al., EMBO J. 10: 4025–4031, 1991).
These results indicate that hTNFα plays an important role as a direct or indirect regulator controlling inflammatory cytokines in rheumatoid arthritis. Accordingly, there has been a need to develop a monoclonal antibody having high selectivity and reactivity against hTNFα for the purpose of treating rheumatoid arthritis.